Stable HIV decoy receptor expression after in vivo HSC transduction in mice and NHPs: Safety and efficacy in protection from SHIV

Chang Li; Anna Kate Anderson; Hongjie Wang; Sucheol Gil; Jiho Kim; Lishan Huang; Audrey Germond; Audrey Baldessari; Veronica Nelson; Katharine J Bar; Christopher W Peterson; John Bui; Hans-Peter Kiem; André Lieber

doi:10.1016/j.ymthe.2023.02.002

Stable HIV decoy receptor expression after in vivo HSC transduction in mice and NHPs: Safety and efficacy in protection from SHIV

Mol Ther. 2023 Apr 5;31(4):1059-1073. doi: 10.1016/j.ymthe.2023.02.002. Epub 2023 Feb 9.

Authors

Affiliations

¹ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA. Electronic address: cli1239@uw.edu.
² Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
³ Washington National Primate Research Center, Division of Regenerative Medicine and Gene Therapy, Seattle, WA 98195, USA.
⁴ Stem and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Stem and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Washington National Primate Research Center, Division of Regenerative Medicine and Gene Therapy, Seattle, WA 98195, USA.
⁷ Stem and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, Division of Allergy and Infection Diseases, University of Washington, Seattle, WA 98195, USA.
⁸ Stem and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Washington National Primate Research Center, Division of Regenerative Medicine and Gene Therapy, Seattle, WA 98195, USA; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA 98195, USA.
⁹ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Washington National Primate Research Center, Division of Regenerative Medicine and Gene Therapy, Seattle, WA 98195, USA. Electronic address: lieber00@uw.edu.

Abstract

We aim to develop an in vivo hematopoietic stem cell (HSC) gene therapy approach for persistent control/protection of HIV-1 infection based on the stable expression of a secreted decoy protein for HIV receptors CD4 and CCR5 (eCD4-Ig) from blood cells. HSCs in mice and a rhesus macaque were mobilized from the bone marrow and transduced by an intravenous injection of HSC-tropic, integrating HDAd5/35++ vectors expressing rhesus eCD4-Ig. In vivo HSC transduction/selection resulted in stable serum eCD4-Ig levels of ∼100 μg/mL (mice) and >20 μg/mL (rhesus) with half maximal inhibitory concentrations (IC₅₀s) of 1 μg/mL measured by an HIV neutralization assay. After simian-human-immunodeficiency virus D (SHIV.D) challenge of rhesus macaques injected with HDAd-eCD4-Ig or a control HDAd5/35++ vector, peak plasma viral load levels were ∼50-fold lower in the eCD4-Ig-expressing animal. Furthermore, the viral load was lower in tissues with the highest eCD4-Ig expression, specifically the spleen and lymph nodes. SHIV.D challenge triggered a selective expansion of transduced CD4⁺CCR5⁺ cells, thereby increasing serum eCD4-Ig levels. The latter, however, broke immune tolerance and triggered anti-eCD4-Ig antibody responses, which could have contributed to the inability to eliminate SHIV.D. Our data will guide us in the improvement of the in vivo approach. Clearly, our conclusions need to be validated in larger animal cohorts.

Keywords: eCD4-Ig decoy receptor; gene therapy; helper-dependent adenovirus vectors; hematopoietic stem cells; in vivo; mobilization; rhesus macaques; simian-human immunodeficiency virus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
HIV Infections*
HIV-1*
Hematopoietic Stem Cells
Humans
Macaca mulatta
Mice
Simian Acquired Immunodeficiency Syndrome* / therapy
Simian Immunodeficiency Virus* / genetics

Abstract

Publication types

MeSH terms

Grants and funding